(2-Benzyloxyphenyl)acetyl (BnPAc): A Participating Relay Protecting Group for Diastereoselective Glycosylation and the Synthesis of 1,2-trans Glycosyl Esters

Article abstract of DOI:10.1055/s-0037-1610255

The (2-benzyloxyphenyl)acetyl group has been identified as a new protecting group for hydroxyl functions. Various alcohols could be easily protected with high yields, and deprotection was achieved by a relay approach using Pd/H ₂ in combination with 1,8-bis(dimethylamino)naphthalene, conditions that are orthogonal to ester groups. The new protecting group is stable in glycosylation reactions demonstrating an effective neighboring group participation leading to the exclusive formation of 1,2-trans glycosides and glycosyl esters.

Full text of DOI:10.1055/s-0037-1610255

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
J. Weber et al.
Letter
Synlett
(2-Benzyloxyphenyl)acetyl (BnPAc): A Participating Relay
Protecting Group for Diastereoselective Glycosylation and the
Synthesis of 1,2-trans Glycosyl Esters
Julia Webera
BnO
BnO
BnO
O
Simon Krautera,b
Theresa Schwarza
Christian Hametnera
BnO
BnO
O
BnO
BnO
R’
O
O
O
O
BnO
BnO
SEt
O
R’OH
O
R
O
H
O
OBn
O
OBn
OBn
Hannes Mikula*a
0
0
0
0
0-
0
0
2
9-
2
1
8
9-
7
2
2
BnPAc
anchimeric
assistance
a Institute of Applied Synthetic Chemistry Vienna University of
Technology (TU Wien), Getreidemarkt 9, 1060 Vienna, Austria
hannes.mikula@tuwien.ac.at
b Division of Organic Chemistry, University of Natural Resources
and Life Sciences, Vienna (BOKU), Muthgasse 18, 1190 Vienna,
Austria
HO
HO
O
HO
HO
O
O
HO
HO
O
and
R’
HO
R’
HO
O
1,2-trans glycosides
1,2-trans glycosyl esters
Received: 19.06.2018
Accepted after revision: 20.07.2018
Published online: 06.09.2018
only partly meet the above-mentioned requirements. As a
consequence, there is still a continuous need for the devel-
opment of new PGs in carbohydrate chemistry.
DOI: 10.1055/s-0037-1610255; Art ID: st-2018-d0379-l
Relay cleavage is a valuable tool for designing new PGs.
In relay cleavage PGs have an auxiliary group that is stable
under a wide range of conditions. Cleavage is initiated by a
chemical transformation of this group leading to a readily
cleavable form or even resulting in spontaneous deprotec-
tion under mild conditions. Although relay deprotection
lengthens the cleavage process by an extra step of activa-
tion, this is compensated by the added measure of orthogo-
nality to other functional and protecting groups.4 Based on
this principle a variety of PGs has been introduced so far,
including AZMB,6 AMPA,7 APAc,8 POMB,9 CAMB,10 NPAc,11
PAC,12 and TMBPP.13 However, deprotection by hydrogeno-
lysis is represented only rarely within the class of relay pro-
tecting groups, even though it is one of the most efficient
and thereby common methods for deprotection, consider-
ing the wide application of benzyl protection.4,5 Hydro-
genolysis has been described for the removal of the PAC
group and its advancement, the TMBPP (3-[2-(benzyloxy)-
4,6-dimethylphenyl]-3,3-dimethylpropanoyl) group, which
has furthermore been shown to be an efficient neighboring
participating group in glycosylation reactions. However, the
use of TMBPP leads to failures in coupling reactions with
bulky acceptors of low reactivity.13 Moreover, the reagent
required for the introduction of TMBPP either needs to be
prepared in three steps from an expensive intermediate or
four steps from readily available compounds.
Abstract The (2-benzyloxyphenyl)acetyl group has been identified as
a new protecting group for hydroxyl functions. Various alcohols could
be easily protected with high yields, and deprotection was achieved by
a relay approach using Pd/H2 in combination with 1,8-bis(dimethylami-
no)naphthalene, conditions that are orthogonal to ester groups. The
new protecting group is stable in glycosylation reactions demonstrat-
ing an effective neighboring group participation leading to the exclu-
sive formation of 1,2-trans glycosides and glycosyl esters.
Key words protecting groups, relay deprotection, neighboring group
participation, anchimeric assistance, glycosides, glycosyl esters
Protecting groups (PGs) are crucial for the synthesis of
complex and multifunctional organic compounds. Especial-
ly in the field of carbohydrate chemistry, the use of PGs and
protecting group patterns for the differentiation of multiple
hydroxyl groups in regard to chemo- and regioselectivity
plays a pivotal role.1,2 Routinely, in oligosaccharide synthe-
sis there are only a few commonly used persistent PGs (ace-
tyl, benzyl, or benzoyl groups); whereas a variety of tempo-
rary PGs depending on the structure of the target molecule
and the type of the persistent PGs are applied.3 The require-
ments for an ideal PG are: (i) simple introduction with read-
ily available, inexpensive reagents, (ii) high stability during
chemical transformations and purification steps, and (iii)
selective and efficient deprotection under mild conditions
without affecting other functional groups.4 Although a vast
number of PGs has been reported,4,5 only few have found
wide application, mostly due to the fact that many groups
Herein, we introduce (2-benzyloxyphenyl)acetyl as a
new participating protecting group that can be cleaved in
the presence of either esters or benzyl ethers.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
J. Weber et al.
Letter
Synlett
(2-Benzyloxyphenyl)acetic acid (BnPAcOH (1), Scheme
1) was prepared as a reagent for the introduction of BnPAc
starting by reacting commercially available and inexpen-
sive methyl 2-(2-hydroxyphenyl)acetate with benzyl
bromide in the presence of potassium carbonate in DMF,
followed by saponification of the methyl ester with potassi-
um hydroxide in methanol. Notably, 1 can be obtained
without purification of the benzylated intermediate and
without any chromatography in 80% yield.
OH
OBnPAc
i
94%
2
3
7
i
OH
OBnPAc
93%
8
HO
BnPAcO
i
O
O
BnO
BnO
BnO
BnO
82%
4
5
9
OH COOMe
OBn
i) K2CO3, BnBr, DMF
ii) KOH, MeOH
OH
O
O
80% (2 steps)
O
O
O
i
O
O
• ‘one-pot’ procedure
• no chromatography required
BnPAcOH (1)
86%
O
O
HO
BnPAcO
O
O
10
Scheme 1 Synthesis of (2-benzyloxyphenyl)acetic acid
BnO
BnO
i
O
O
BnO
BnO
BnO
BnO
BnPAcO
BnPAc protection of different alcohols 2–6 was readily
achieved by reaction with BnPAcOH (1) in the presence of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and
4-(dimethylamino)pyridine (DMAP) in CH2Cl2 (General Pro-
cedure A).14 Esters 7–1115–19 were obtained in good yields
(82–94%, Scheme 2).
SEt
SEt
88%
HO
6
11
Scheme 2 Introduction of BnPAc. Reagents and conditions: i. BnPAcOH
(1), EDC, DMAP, CH2Cl2.
Removal of the BnPAc group was accomplished either
by using a relay approach (General Procedure B1) applying
catalytic hydrogenation in combination with 1,8-bis(di-
methylamino)naphthalene (bDMAN)20 or by reaction with
K2CO3 in methanol (General Procedure B2).21 Compounds 7,
8, and 10 were deprotected using procedure B1 affording
the corresponding alcohols 2, 3, and 5, respectively, and
benzofuran-2(3H)-one as byproduct formed by intramolec-
ular cyclization of the intermediate (2-hydroxyphenyl)acetyl
group leading to final deprotection (Table 1).8 As compound
9 is sensitive to hydrogenolysis, procedure B2 was applied
to obtain 422 in 90% without affecting the glucal double
bond (Table 1, entry 3).
After having established a simple method for the intro-
duction and two orthogonal procedures for the removal of
BnPAc, we tested its applicability in diastereoselective gly-
cosylation reactions exploiting the neighboring group par-
ticipation (anchimeric assistance) of BnPAc (Scheme 3, a).
Thioglycoside 11 was activated with NIS and TfOH23 and re-
acted with phenylethanol (Scheme 3, b) and glucosyl accep-
tor 14 (Scheme 3, c), leading exclusively to the formation of
β-glucosides 1224 and 1525 in yields of 88% and 91%, respec-
tively. Simultaneous deprotection of the BnPAc- and Bn-
protected glucoside 12 was achieved in a single step by cat-
alytic hydrogenation followed by reaction with bDMAN
(procedure B1) to obtain glucoside 1326 in 84% yield. Selec-
tive cleavage of the BnPAc-protected OH-group of 15 in the
Table 1 Removal of BnPAc
R
HO
HO
OBn
[Pd/C]
H2
K2CO3
MeOH
+
HO
O
O
bDMAN
R
R
R
O
O
O
O
Entry
Substrate
Procedure
Cleavage conditions
Yield (%)
1
2
3
4
7
8
B1
B1
B2
B1
[Pd/C], H2; then bDMANa
[Pd/C], H2; then bDMANa
K2CO3, MeOH
˃99b
˃99b
90
9
10
[Pd/C], H2; then bDMANa
63
a bDMAN = 1,8-bis(dimethylamino)naphthalene.
b Determined by GC-MS.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
J. Weber et al.
Letter
Synlett
presence of the benzyl groups was carried out applying
procedure B2 to afford disaccharide 1627 (95%).
reaction with 1,8-bis(dimethylamino)naphthalene or by
Zemplén transesterification using K2CO3 in methanol. BnPAc
was furthermore shown to provide efficient anchimeric as-
sistance in glycosylation reactions leading to the formation
of 1,2-trans glycosides with complete diastereoselectivity.
Its cleavage under hydrogenolytic conditions, moreover, en-
ables the synthesis of glycosides in the presence of ester
functionalities or 1,2-trans glucosyl esters. Hence, we are
convinced that the BnPAc group represents a valuable tool,
especially in the field of carbohydrate chemistry.
Encouraged by these results, we proceeded to perform a
glycosylation reaction with glucosyl donor 11 and the pro-
tected amino acid 17 as acceptor leading to the formation of
glucosyl ester 1828 with complete β-diastereoselectivity.
Relay deprotection of 18 enabled the simultaneous removal
of BnPAc and the benzyl groups, leading to 1929 in 68%
yield. Notably, ester functionalities and the tert-butyloxy-
carbonyl (Boc)-protected amine were not affected (Scheme
3, d).
Funding Information
a
R’
O
O
O
(RO)n
acceptor
We thank the Austrian Research Promotion Agency (FFG, BRIDGE-
Project 843488) for financial support.
H
O
activation
(RO)n
SEt
O
)(
OBn
BnPAcO
anchimeric
assistance
(blocking axial position)
2-O-BnPAc
glycosyl donor
Supporting Information
Supporting information for this article is available online at
RO
b
https://doi.org/10.1055/s-0037-1610255.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
OH
i
O
RO
RO
O
11
88%
R’O
References and Notes
diastereoselective
1,2-trans glycosylation
12 R = Bn, R’ = BnPAc
13 R = H, R’ = H
(1) The Organic Chemistry of Sugars; Levy, D.; Fügedi, P., Eds.; CRC
Press: Boca Raton, FL, 2005.
(2) Guo, J.; Ye, X.-S. Molecules 2010, 15, 7235.
ii, 84%
simultaneous
cleavage of
(3) Ágoston, K.; Streicher, H.; Fügedi, P. Tetrahedron: Asymmetry
2016, 27, 707.
Bn and BnPAc
BnO
HO
c
(4) Kocienski, P. J. Protecting Groups; Kocieński, P. J., Ed.; Thieme:
Stuttgart, 2005, 3rd ed..
(5) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis; John Wiley and Sons: Hoboken, NJ, 2006, 4th
ed..
O
BnO
O
BnO
i
O
BnO
BnO
11
RO
BnO
BnO
91%
O
BnO
OMe
BnO
14
OMe
(6) Wada, T.; Ohkubo, A.; Mochizuki, A.; Sekine, M. Tetrahedron
Lett. 2001, 42, 1069.
(7) Xu, J.; Guo, Z. Carbohydr. Res. 2002, 337, 87.
diastereoselective synthesis of disaccharides
and selective cleavage of BnPAc
15 R = BnPAc
16 R = H
iii, 95%
(8) Arranz, E.; Boons, G.-J. Tetrahedron Lett. 2001, 42, 6469.
(9) Vatèle, J.-M. Tetrahedron Lett. 2005, 46, 2299.
OAc
RO
d
OAc
(10) Ziegler, T.; Pantkowski, G. Liebigs Ann. Chem. 1994, 659.
(11) Daragics, K.; Fügedi, P. Org. Lett. 2010, 12, 2076.
(12) Watanabe, Y.; Ishimaru, M.; Ozaki, S. Chem. Lett. 1994, 23, 2163.
(13) Crich, D.; Cai, F. Org. Lett. 2007, 9, 1613.
O
RO
RO
i
62%
O
11
HO
N
N
R’O
O
O
O
O
O
O
(14) General Procedure A: Introduction of BnPAc
Alcohol (0.5 mmol, 1 equiv), BnPAcOH (0.6 mmol, 1.2 equiv),
and DMAP (0.05 mmol, 0.1 equiv) were dissolved in dry CH2Cl2
(3 mL) and the mixture cooled to 0 °C. After addition of EDCI
(0.6 mmol, 1.2 equiv), the reaction mixture was stirred at r.t.
until completion of the reaction. The reaction mixture was
diluted with CH2Cl2 (10 mL) and washed with 1 M HCl (2 ×
10 mL), saturated NaHCO3 solution (2 × 10 mL), and brine
(10 mL). The aqueous phases were extracted with CH2Cl2 (5 mL)
after each washing step. The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (gradient
elution hexanes/EtOAc) to yield the desired product.
(15) (2-Benzyloxyphenyl) Acetic Acid, Cyclohexyl Ester 7
Starting from cyclohexanol (100 mg, 0.1 mmol) and following
general procedure A BnPAc ester 7 was obtained as a white solid
(306 mg, 94%). For analytical data see Supporting Information.
17
BnO
18 R = Bn, R’= BnPAc
19 R = H, R’ = H
glucosyl
donor
ii, 68%
11
O
BnO
BnO
selective deprotection in the presence
of ester functionalities
SEt
BnPAcO
Scheme 3 Diastereoselective glycosylation using the 2-O-BnPAc-
glucosyl donor 11. (a) Anchimeric assistance of BnPAc; (b) BnPAc and
benzyl ethers can be deprotected simultaneously; (c) selective depro-
tection of BnPAc in the presence of benzyl ethers; (d) synthesis of an
amino acid glucosyl ester. Reagents and conditions: i. NIS/TfOH, CH2Cl2;
ii. [Pd/C], H2, then bDMAN; iii. K2CO3, MeOH.
In summary, BnPAc is a stable protecting group that can
easily be introduced in high yields and either cleaved by a
relay approach using catalytic hydrogenation followed by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
J. Weber et al.
Letter
Synlett
(16) (2-Benzyloxyphenyl) Acetic Acid, Cyclohexylmethyl Ester 8
Starting from cyclohexyl methanol (114 mg, 0.1 mmol) and fol-
lowing general procedure A BnPAc ester 8 was obtained as a
white solid (315 mg, 93%). For analytical data see Supporting
Information.
(23) General Procedure C: Glycosylation with Donor 11
To a solution of the acceptor (680 μmol, 2.5 equiv) and glucosyl
donor 11 (200 mg, 272 μmol, 1 equiv) in dry CH2Cl2 (5 mL)
molecular sieves (3 Å, 100 mg/mL) were added, and the reaction
mixture was stirred for 2 h at r.t. After cooling to –10 °C, N-iodo-
succinimide (133 mg, 544 μmol, 2 equiv), followed by trifluoro-
methanesulfonic acid (5 μL, 54 μmol, 0.2 equiv) were added,
and stirring was continued for 16 h. The reaction was quenched
by addition of saturated aqueous NaHCO3 and Na2SO3 solutions
(1:1, 1 mL), then the reaction solution was diluted with CH2Cl2
(4 mL) and filtered through Celite®. The filtrate was washed
with water (5 mL) and brine (3 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (hexanes/EtOAc gradient
elution) to obtain the desired product.
(17) (2-Benzyloxyphenyl) Acetic Acid, 3,4-di-O-Benzyl Glucuronal
Ester 9
Starting from 3,4-di-O-benzyl glucuronal (200 mg, 0.61 mmol)
and following general procedure A BnPAc ester 9 was obtained
(276 mg, 82%). For analytical data see Supporting Information.
(18) (2-Benzyloxyphenyl) Acetic Acid, 1,2,5,6-Diisopropylidene
Glucosyl Ester 10
Starting from diacetone-D-glucose (50 mg, 0.19 mmol) and fol-
lowing general procedure A BnPAc ester 10 was obtained
(80 mg, 86%). For analytical data see Supporting Information.
(19) Ethyl 3,4,6-Tri-O-benzyl-2-O-[(2-benzyloxyphenyl)acetyl]-1-
thio-β,D-glucoside (11)
(24) 2-Phenylethyl
3,4,6-Tri-O-benzyl-2-O-[(2-benzyloxy-phe-
nyl)acetyl]-β,D-glucoside (12)
Starting from ethyl 3,4,6-tri-O-benzyl-1-thio-β,D-glucoside
(4.4 g, 9 mmol) and following general procedure A glucosyl
donor 11 was obtained as a white solid (5.2 g, 88%). For analyti-
cal data see Supporting Information.
General procedure C; starting from phenylethanol (83 mg,
0.68 mmol) and glucosyl donor 11 (200 mg, 0.27 mmol) 12 was
obtained as a white solid (90 mg, 88%). For analytical data see
Supporting Information.
(20) General Procedure B1: Deprotection of BnPAc via Catalytic
Hydrogenation
(25) Methyl 2,3,4,9,10,12-Hexa-O-benzyl-8-O-[(2-benzyloxy-phe-
nyl)acetyl]-α,D-gentiobioside (15)
To a solution of the respective BnPAc-protected compound
(0.07 mmol, 1 equiv) in dry ethanol (1.5 mL) one small tip of a
spatula of Pd/C was added under an argon atmosphere. The
argon balloon was changed for a H2 balloon, and the reaction
mixture was stirred for 3–6 h at r.t. The reaction mixture was
filtered through a syringe filter, proton sponge (1 equiv) was
added to the filtrate, and the reaction solution was heated up to
80 °C until completion of the reaction (4–8 h). The reaction
mixture was concentrated, and the residue was purified either
by flash chromatography (gradient elution hexanes/EtOAc) or
by preparative HPLC (H2O/MeCN) to yield the corresponding
product.
General procedure C; starting from glucosyl donor 11 (60 mg,
0.08 mmol) and acceptor 14 (93 mg, 0.2 mmol) 15 (83 mg, 91%)
was obtained. For analytical data see Supporting Information.
(26) 2-Phenylethyl-β,D-glucoside (13)
Starting from compound 12 (36 mg, 0.05 mmol) and following
general procedure B1 13 was obtained as a white solid (12 mg,
84%). Analytical data matched those reported in the literature.30
(27) Methyl 2,3,4,9,10,12-Hexa-O-benzyl-α,D-gentiobioside (16)
Starting from compound 15 (50 mg, 0.04 mmol) and following
general procedure B2 16 was obtained as a white solid (37 mg,
95%). For analytical data see Supporting Information.
(28) trans-N-(tert-Butoxycarbonyl)-4-acetoxy-L-proline,
3,4,6-
(21) General Procedure B2: Deprotection of BnPAc via basic
hydrolysis
Tri-O-benzyl-2-O-[(2-benzyloxyphenyl) Acetyl]-β,D-glucosyl
Ester (18)
To a solution of the respective BnPAc-protected compound in
dry methanol K2CO3 (0.5 equiv) was added. The reaction
mixture was stirred for 16 h at room temperature. In some
cases, further addition of 0.5 equiv NaOMe was necessary for
completion of the reaction. The reaction mixture was filtered,
concentrated and the residue was purified by flash chromatog-
raphy (gradient elution hexanes/EtOAc) or by preparative-HPLC
(H2O/MeCN) to obtain the desired product.
General procedure C; starting from glucosyl donor 11 (100 mg,
0.14 mmol) and acceptor 17 (57 mg, 0.21 mmol) 18 (80 mg,
62%) was obtained. For analytical data see Supporting Informa-
tion..
(29) trans-N-(tert-Butoxycarbonyl)-4-acetoxy-L-proline, β,D-Glu-
cosyl Ester (19)
Starting from compound 18 (35 mg, 0.04 mmol) and following
general procedure B1 19 was obtained as a colourless solid
(11 mg, 68%).
(22) Mikula, H.; Matscheko, D.; Schwarz, M.; Hametner, C.; Fröhlich,
J. Carbohydr. Res. 2013, 370, 19.
(30) Guo, Y.; Zhao, Y.; Zheng, C.; Meng, Y.; Yang, Y. Chem. Pharm.
Bull. 2010, 58, 1627.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D